tbuckley/cabot-search huggingface dataset:
Inhibition of myeloperoxidase enhances immune checkpoint therapy for melanoma
Authors: Tracy W Liu, Seth T Gammon, Ping Yang, Wencai Ma, Jing Wang, David Piwnica-Worms
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background The presence of a highly immunosuppressive tumor microenvironment has limited the success of immune checkpoint therapy (ICT). Immune suppressing myeloid cells with increased production of reactive oxygen species are critical drivers of this immunosuppressive tumor microenvironment. Strategies to limit these immune suppressing myeloid cells are needed to enhance response to ICT. Methods To evaluate the contribution of myeloperoxidase (MPO), a myeloid lineage-restricted enzyme and a major source of reactive oxygen species, to mediating ICT response, we compared treatment outcome and immune composition in wild-type, MPO-deficient ( MPO −/− ), and MPO inhibitor-treated wild-type mice using established primary melanoma models. Results Tumor growth and survival studies demonstrated that either host deficiency ( MPO −/− ) or pharmacological inhibition of MPO enhanced ICT response in two preclinical models of established primary melanoma in aged animals. The tumor microenvironment and systemic immune landscape underwent striking changes in infiltration of myeloid cells, T cells, B cells, and dendritic cells in MPO −/− mice; furthermore, a significant increase in myeloid cells was observed in ICT non-responders. The contribution of CD4 + T cells and NK cells during ICT response also changed in MPO −/− mice. Interestingly, MPO enzymatic activity, but not protein, was increased in CD11b + Ly6G + myeloid cells isolated from marrow, spleen, and peritoneal cavities of mice bearing untreated melanoma, indicating systemic activation of innate immunity. Notably, repurposing MPO-specific inhibitors (verdiperstat, AZD5904) in combination with ICT pointedly enhanced response rates above ICT alone. Indeed, long-term survival was 100% in the YUMM3.3 melanoma model on treatment with verdiperstat plus ICT. Conclusion MPO contributes to ICT resistance in established melanoma. Repurposing MPO-specific inhibitors may provide a promising therapeutic strategy to enhance ICT response.
Experiences of parents of trans young people accessing Australian health services for their child: Findings from Trans Pathways
Authors: Georgia Chaplyn, Liz A. Saunders, Ashleigh Lin, Angus Cook, Sam Winter, Natalie Gasson, Vanessa Watson, Dani Wright Toussaint, Penelope Strauss
Journal: International Journal of Transgender Health (2023)

Many trans young people seek mental health support and gender-affirming medical interventions including puberty suppression, gender-affirming hormones and/or surgeries. Trans young people and their parents face multiple barriers in accessing gender-affirming care and mental health support, however little is known about the parent perspective on accessing services for their trans child.
Imagining the future self through thought experiments
Authors: Kentaro Miyamoto, Matthew F.S. Rushworth, Nicholas Shea
Journal: Trends in Cognitive Sciences (2023)

The ability of the mind to conceptualize what is not present is essential. It allows us to reason counterfactually about what might have happened had events unfolded differently or had another course of action been taken. It allows us to think about what might happen - to perform 'Gedankenexperimente' (thought experiments) - before we act. However, the cognitive and neural mechanisms mediating this ability are poorly understood. We suggest that the frontopolar cortex (FPC) keeps track of and evaluates alternative choices (what we might have done), whereas the anterior lateral prefrontal cortex (alPFC) compares simulations of possible future scenarios (what we might do) and evaluates their reward values. Together, these brain regions support the construction of suppositional scenarios.
Aerobic exercise and scaffolds with hierarchical porosity synergistically promote functional recovery post volumetric muscle loss
Authors: Yori Endo, Mohamadmahdi Samandari, Mehran Karvar, Azadeh Mostafavi, Jacob Quint, Chiara Rinoldi, Iman K. Yazdi, Wojciech Swieszkowski, Joshua Mauney, Shailesh Agarwal, Ali Tamayol, Indranil Sinha
Journal: Biomaterials (2023)
Neurovascular adaptations modulating cognition, mood, and stress responses
Authors: Laurence Dion-Albert, Katarzyna A. Dudek, Scott J. Russo, Matthew Campbell, Caroline Menard
Journal: Trends in Neurosciences (2023)

The neurovascular unit (NVU) is a dynamic center for substance exchange between the blood and the brain, making it an essential gatekeeper for central nervous system (CNS) homeostasis. Recent evidence supports a role for the NVU in modulating brain function and cognition. In addition, alterations in NVU processes are observed in response to stress, although the mechanisms via which they can affect mood and cognitive functions remain elusive. Here, we summarize recent studies of neurovascular regulation of emotional processes and cognitive function, including under stressful conditions. We also highlight relevant RNA-sequencing (RNA-seq) databases aiming to profile the NVU along with innovative tools to study and manipulate NVU function that can be exploited in the context of cognition and stress research throughout development, aging, or brain disorders.
First report of PhALLCON: A phase 3 study comparing ponatinib (pon) vs imatinib (im) in newly diagnosed patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL).
Authors: Elias Jabbour, Hagop M. Kantarjian, Ibrahim Aldoss, Pau Montesinos, Jessica Taft Leonard, David Gomez-Almaguer, Maria R. Baer, Carlo Gambacorti-Passerini, James McCloskey, Yosuke Minami, Cristina Papayannidis, Vanderson Geraldo Rocha, Philippe Rousselot, Pankit Vachhani, Eunice S. Wang, Bingxia Wang, Meliessa Hennessy, Alexander Vorog, Niti Patel, Josep-Maria Ribera
Journal: Journal of Clinical Oncology (2023)

398868 Background: The standard of care in patients (pts) with newly diagnosed (dx) Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) is BCR::ABL1 tyrosine kinase inhibitors (TKIs) in combination with chemotherapy (chemo) or steroids. Treated with 1st- or 2nd-generation TKIs, pts eventually progress due to emergence of resistance. Multiple studies have reported promising minimal residual disease (MRD) negativity (neg) rates and survival outcomes with pon in combination with chemo or chemo-free regimens. PhALLCON (NCT03589326), the first randomized study comparing TKIs in pts with Ph+ALL, evaluates pon vs im in combination with reduced-intensity chemo. Methods: This phase 3 open-label trial randomized adult newly dx Ph+ALL pts 2:1 to receive pon (30 mg once daily [QD]) or im (600 mg QD) with reduced-intensity chemo through end of induction (EOI; Cycles 1–3), consolidation (Cycles 4–9), and post-consolidation (Cycles 10–20). After Cycle 20, pts received single-agent pon or im until disease progression or unacceptable toxicity. The composite primary endpoint was MRD-neg ( BCR:: ABL1 ≤0.01% ) complete remission (CR) for 4 weeks at EOI. Event-free survival (EFS: any cause death, failure to achieve CR by EOI, relapse from CR) was a key secondary endpoint. Results: 245 pts were randomized to pon (n=164) or im (n=81); median age was 54 y (37% ≥60 y). At data cutoff (Aug 2022), 78 pts (pon vs im: 42% vs 12%) were on study treatment; the top 3 reasons for discontinuation were hematopoietic stem cell transplantation (31% vs 37%), adverse events (12% vs 12%), and lack of efficacy (7% vs 26%). Median follow-up was 20 mo vs 18 mo (pon vs im). The primary endpoint was met (Table) by significantly higher MRD-neg CR rate for pon vs im (34.4% vs 16.7%; p=0.0021). Survival data were not mature; however, the median EFS was reached in im and not in pon, with a trend toward improvement (HR=0.652, 95% CI 0.385–1.104). Time to treatment failure reported an improvement as well (HR=0.455). The treatment-emergent adverse event (TEAE) rates (any grade [Gr] and Gr3/4/5) were comparable between treatment arms. Arterial occlusive events (AOEs) were infrequent and similar between the arms (Table). Conclusions: Pon was superior to im in combination with reduced-intensity chemo in pts with newly dx Ph+ALL, with a significantly higher MRD-neg CR rate at the EOI. Pon was associated with deeper and more durable responses, with a trend toward improved EFS and comparable safety vs im. Clinical trial information: NCT03589326 . [Table: see text]
Author Correction: The contribution of amyloid deposition in the aortic valve to calcification and aortic stenosis
Authors: Karan Sud, Navneet Narula, Elena Aikawa, Eloisa Arbustini, Philippe Pibarot, Giampaolo Merlini, Robert S. Rosenson, Surya V. Seshan, Edgar Argulian, Amir Ahmadi, Fang Zhou, Andre L. Moreira, Nancy Côté, Sotirios Tsimikas, Valentin Fuster, Sam Gandy, Robert O. Bonow, Olga Gursky, Jagat Narula
Journal: Nature Reviews Cardiology (2023)
Bioceramic scaffolds with triply periodic minimal surface architectures guide early-stage bone regeneration
Authors: Miaoda Shen, Yifan Li, Fengling Lu, Yahui Gou, Cheng Zhong, Shukun He, Chenchen Zhao, Guojing Yang, Lei Zhang, Xianyan Yang, Zhongru Gou, Sanzhong Xu
Journal: Bioactive Materials (2023)

The pore architecture of porous scaffolds is a critical factor in osteogenesis, but it is a challenge to precisely configure strut-based scaffolds because of the inevitable filament corner and pore geometry deformation. This study provides a pore architecture tailoring strategy in which a series of Mg-doped wollastonite scaffolds with fully interconnected pore networks and curved pore architectures called triply periodic minimal surfaces (TPMS), which are similar to cancellous bone, are fabricated by a digital light processing technique. The sheet-TPMS pore geometries (s-Diamond, s-Gyroid) contribute to a 3‒4-fold higher initial compressive strength and 20%-40% faster Mg-ion-release rate compared to the other-TPMS scaffolds, including Diamond, Gyroid, and the Schoen's I-graph-Wrapped Package (IWP) in vitro. However, we found that Gyroid and Diamond pore scaffolds can significantly induce osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Analyses of rabbit experiments in vivo show that the regeneration of bone tissue in the sheet-TPMS pore geometry is delayed; on the other hand, Diamond and Gyroid pore scaffolds show notable neo-bone tissue in the center pore regions during the early stages (3-5 weeks) and the bone tissue uniformly fills the whole porous network after 7 weeks. Collectively, the design methods in this study provide an important perspective for optimizing the pore architecture design of bioceramic scaffolds to accelerate the rate of osteogenesis and promote the clinical translation of bioceramic scaffolds in the repair of bone defects.
Long-term participant retention and engagement patterns in an app and wearable-based multinational remote digital depression study
Authors: Yuezhou Zhang, Abhishek Pratap, Amos A. Folarin, Shaoxiong Sun, Nicholas Cummins, Faith Matcham, Srinivasan Vairavan, Judith Dineley, Yatharth Ranjan, Zulqarnain Rashid, Pauline Conde, Callum Stewart, Katie M. White, Carolin Oetzmann, Alina Ivan, Femke Lamers, Sara Siddi, Carla Hernández Rambla, Sara Simblett, Raluca Nica, David C. Mohr, Inez Myin-Germeys, Til Wykes, Josep Maria Haro, Brenda W. J. H. Penninx, Peter Annas, Vaibhav A. Narayan, Matthew Hotopf, Richard J. B. Dobson
Journal: npj Digital Medicine (2023)

Abstract Recent growth in digital technologies has enabled the recruitment and monitoring of large and diverse populations in remote health studies. However, the generalizability of inference drawn from remotely collected health data could be severely impacted by uneven participant engagement and attrition over the course of the study. We report findings on long-term participant retention and engagement patterns in a large multinational observational digital study for depression containing active (surveys) and passive sensor data collected via Android smartphones, and Fitbit devices from 614 participants for up to 2 years. Majority of participants (67.6%) continued to remain engaged in the study after 43 weeks. Unsupervised clustering of participants’ study apps and Fitbit usage data showed 3 distinct engagement subgroups for each data stream. We found: (i) the least engaged group had the highest depression severity (4 PHQ8 points higher) across all data streams; (ii) the least engaged group (completed 4 bi-weekly surveys) took significantly longer to respond to survey notifications (3.8 h more) and were 5 years younger compared to the most engaged group (completed 20 bi-weekly surveys); and (iii) a considerable proportion (44.6%) of the participants who stopped completing surveys after 8 weeks continued to share passive Fitbit data for significantly longer (average 42 weeks). Additionally, multivariate survival models showed participants’ age, ownership and brand of smartphones, and recruitment sites to be associated with retention in the study. Together these findings could inform the design of future digital health studies to enable equitable and balanced data collection from diverse populations.
Consensus Statement on the definition and classification of metabolic hyperferritinaemia
Authors: Luca Valenti, Elena Corradini, Leon A. Adams, Elmar Aigner, Saleh Alqahtani, Marco Arrese, Edouard Bardou-Jacquet, Elisabetta Bugianesi, Jose-Manuel Fernandez-Real, Domenico Girelli, Hannes Hagström, Benjamin Henninger, Kris Kowdley, Guido Ligabue, Donald McClain, Fabrice Lainé, Koji Miyanishi, Martina U. Muckenthaler, Alessia Pagani, Patrizia Pedrotti, Antonello Pietrangelo, Daniele Prati, John D. Ryan, Laura Silvestri, C. Wendy Spearman, Per Stål, Emmanuel A. Tsochatzis, Francesca Vinchi, Ming-Hua Zheng, Heinz Zoller
Journal: Nature Reviews Endocrinology (2023)
Targeting histone deacetylases for cancer therapy: Trends and challenges
Authors: Tao Liang, Fengli Wang, Reham M. Elhassan, Yongmei Cheng, Xiaolei Tang, Wengang Chen, Hao Fang, Xuben Hou
Journal: Acta Pharmaceutica Sinica B (2023)

Dysregulation of histone deacetylases (HDACs) is closely related to tumor development and progression. As promising anticancer targets, HDACs have gained a great deal of research interests and two decades of effort has led to the approval of five HDAC inhibitors (HDACis). However, currently traditional HDACis, although effective in approved indications, exhibit severe off-target toxicities and low sensitivities against solid tumors, which have urged the development of next-generation of HDACi. This review investigates the biological functions of HDACs, the roles of HDACs in oncogenesis, the structural features of different HDAC isoforms, isoform-selective inhibitors, combination therapies, multitarget agents and HDAC PROTACs. We hope these data could inspire readers with new ideas to develop novel HDACi with good isoform selectivity, efficient anticancer effect, attenuated adverse effect and reduced drug resistance.
A systems immunology study comparing innate and adaptive immune responses in adults to COVID-19 mRNA and adenovirus vectored vaccines
Authors: Feargal J. Ryan, Todd S. Norton, Conor McCafferty, Stephen J. Blake, Natalie E. Stevens, Jane James, Georgina L. Eden, Yee C. Tee, Saoirse C. Benson, Makutiro G. Masavuli, Arthur E.L. Yeow, Arunasingam Abayasingam, David Agapiou, Hannah Stevens, Jana Zecha, Nicole L. Messina, Nigel Curtis, Vera Ignjatovic, Paul Monagle, Huyen Tran, James D. McFadyen, Rowena A. Bull, Branka Grubor-Bauk, Miriam A. Lynn, Rochelle Botten, Simone E. Barry, David J. Lynn
Journal: Cell Reports Medicine (2023)

Identifying the molecular mechanisms that promote optimal immune responses to coronavirus disease 2019 (COVID-19) vaccination is critical for future rational vaccine design. Here, we longitudinally profile innate and adaptive immune responses in 102 adults after the first, second, and third doses of mRNA or adenovirus-vectored COVID-19 vaccines. Using a multi-omics approach, we identify key differences in the immune responses induced by ChAdOx1-S and BNT162b2 that correlate with antigen-specific antibody and T cell responses or vaccine reactogenicity. Unexpectedly, we observe that vaccination with ChAdOx1-S, but not BNT162b2, induces an adenoviral vector-specific memory response after the first dose, which correlates with the expression of proteins with roles in thrombosis with potential implications for thrombosis with thrombocytopenia syndrome (TTS), a rare but serious adverse event linked to adenovirus-vectored vaccines. The COVID-19 Vaccine Immune Responses Study thus represents a major resource that can be used to understand the immunogenicity and reactogenicity of these COVID-19 vaccines.
Risk factors associated with mortality among elderly patients with COVID-19: Data from 55 intensive care units in Spain
Authors: C. Cilloniz, A. Motos, J.M. Pericàs, T.G. Castañeda, A. Gabarrús, R. Ferrer, D. García-Gasulla, O. Peñuelas, D. de Gonzalo-Calvo, L. Fernandez-Barat, F. Barbé, A. Torres
Journal: Pulmonology (2023)

Critically-ill elderly ICU patients with COVID-19 have poor outcomes. We aimed to compare the rates of in-hospital mortality between non-elderly and elderly critically-ill COVID-19 ventilated patients, as well as to analyze the characteristics, secondary outcomes and independent risk factors associated with in-hospital mortality of elderly ventilated patients. We conducted a multicentre, observational cohort study including consecutive critically-ill patients admitted to 55 Spanish ICUs due to severe COVID-19 requiring mechanical ventilation (non-invasive respiratory support [NIRS; include non-invasive mechanical ventilation and high-flow nasal cannula] and invasive mechanical ventilation [IMV]) between February 2020 and October 2021. Out of 5,090 critically-ill ventilated patients, 1,525 (27%) were aged ≥70 years (554 [36%] received NIRS and 971 [64%] received IMV. In the elderly group, median age was 74 years (interquartile range 72–77) and 68% were male. Overall in-hospital mortality was 31% (23% in patients <70 years and 50% in those ≥70 years; p<0.001). In-hospital mortality in the group ≥70 years significantly varied according to the modality of ventilation (40% in NIRS vs. 55% in IMV group; p<0.001). Factors independently associated with in-hospital mortality in elderly ventilated patients were age (sHR 1.07 [95%CI 1.05–1.10], p<0.001); previous admission within the last 30 days (sHR 1.40 [95%CI 1.04–1.89], p = 0.027); chronic heart disease (sHR 1.21 [95%CI 1.01–1.44], p = 0.041); chronic renal failure (sHR 1.43 [95%CI 1.12- 1.82], p = 0.005); platelet count (sHR 0.98 [95% CI 0.98–0.99], p<0.001); IMV at ICU admission (sHR 1.41 [95% CI 1.16- 1.73], p<0.001); and systemic steroids (sHR 0.61 [95%CI 0.48- 0.77], p<0.001). Amongst critically-ill COVID-19 ventilated patients, those aged ≥70 years presented significantly higher rates of in-hospital mortality than younger patients. Increasing age, previous admission within the last 30 days, chronic heart disease, chronic renal failure, platelet count, IMV at ICU admission and systemic steroids (protective) all comprised independent factors for in-hospital mortality in elderly patients
Nanostructured‐Based Optical Readouts Interfaced with Machine Learning for Identification of Extracellular Vesicles (Adv. Healthcare Mater. 5/2023)
Authors: Carolina del Real Mata, Olivia Jeanne, Mahsa Jalali, Yao Lu, Sara Mahshid
Journal: Advanced Healthcare Materials (2023)

Extracellular Vesicles Identification Extracellular vesicles (EVs) are a potential cancer biomarker enclosing molecular information that hold great promise for early-stage diagnosis and monitoring of cancer. Novel adaptations of optical readouts integrate nanostructures to enhance the sensitivity of the detection of EVs. Furthermore, combining them with machine learning analysis can overcome common challenges in the study of EVs present in liquid biopsy samples. These topics are reviewed in article 2202123 by Sara Mahshid and co-workers. Cover image designed by Ella Maru Studio.
Where Microneedle Meets Biomarkers: Futuristic Application for Diagnosing and Monitoring Localized External Organ Diseases (Adv. Healthcare Mater. 5/2023)
Authors: Achmad Himawan, Lalitkumar K. Vora, Andi Dian Permana, Sumarheni Sudir, Airin R. Nurdin, Ririn Nislawati, Rafikah Hasyim, Christopher J. Scott, Ryan F. Donnelly
Journal: Advanced Healthcare Materials (2023)
Succinic Ester‐Based Shape Memory Gelatin Sponge for Noncompressible Hemorrhage without Hindering Tissue Regeneration (Adv. Healthcare Mater. 5/2023)
Authors: Ye Zhu, Lining Zhang, Wanglin Duan, Sergio Martin‐Saldaña, Chaowei Li, Hongwen Yu, Luyao Feng, Xianpeng Zhang, Baoji Du, Guanying Li, Xifu Zheng, Yazhong Bu
Journal: Advanced Healthcare Materials (2023)

Shape Memory Sponges In article 2202122, Xifu Zheng, Yazhong Bu, and co-workers successfully develop a fast degradable shape memory sponge for noncompressible hemorrhage without hindering tissue regeneration. The resulting sponge possesses high mechanical stability and hemostatic efficiency. Meanwhile, its fast degradation, resulting from succinic esters, leads to fast tissue regeneration when compared with a commercialized sponge. This sponge is composed of components with well-identified biocompatibility, making it very promising in the clinic.
Brill-Zinsser: Still With Us
Authors: Cornelia R. Green
Journal: JAMA (1990)

<h3>To the Editor.—</h3> Epidemic typhus, caused by<i>Rickettsia prowazekii</i>and transmitted by the human body louse, has been associated with wars, famines, concentration camps, and overcrowding since the beginning of recorded history. Brill-Zinsser disease is a recurrent form of epidemic typhus, unrelated to louse infestation, that appears sporadically years after the primary illness.<sup>1</sup>Clinical features are similar to but milder than those of epidemic typhus.<sup>2</sup>In the United States,<i>R prowazekii</i>infections have also been associated with the eastern flying squirrel (<i>Glaucomys volans</i>).<sup>3</sup>Since 1977, at the Centers for Disease Control, the laboratory results and epidemiologic data from four patients have been consistent with Brill-Zinsser disease. We report herein the only case of Brill-Zinsser disease diagnosed at the Centers for Disease Control in the 1980s. A 65-year-old man was hospitalized in April 1989 with a 3-day history of fever and chills. The patient lived in an urban
Changing social-class distribution of heart disease.
Authors: M G Marmot, A M Adelstein, N Robinson, G A Rose
Journal: BMJ (1978)

Analysis of mortality trends over 40 years in England and Wales showed that mortality from coronary heart disease had become progressively more common in working-class men and women than in those from the middle and upper classes. The change was most noticeable for men. Whereas in 1931 and 1951 heart disease was more common in men of social classes I and II, by 1961 it was more common in men of classes IV and V. This change in social-class distribution can only partly be explained by changes in diagnostic methods. The worsening mortality of classes IV and V correlated with relatively more smoking, a higher consumption of sugar, and a lower consumption of wholemeal bread in these classes. There was no correlation between change in heart disease and change in the social-class pattern of fat consumption.
Treatment of chronic hepatitis D with peginterferon lambda—the phase 2 LIMT-1 clinical trial
Authors: Ohad Etzion, Saeed Hamid, Yoav Lurie, Edward J. Gane, David Yardeni, Sarah Duehren, Nimrah Bader, Anat Nevo-Shor, Saleh Muhammad Channa, Scott J. Cotler, Minaz Mawani, Om Parkash, Harel Dahari, Ingrid Choong, Jeffrey S. Glenn
Journal: Hepatology (2023)

HDV infection leads to the most aggressive form of human viral hepatitis for which there is no FDA-approved therapy. PEG IFN-lambda-1a (Lambda) has previously demonstrated a good tolerability profile in HBV and HCV patients compared to PEG IFN-alfa. The goal of Phase 2 LIMT-1 trial was to evaluate the safety and efficacy of Lambda monotherapy in patients with HDV.